The present invention relates to novel heterocyclic compounds and to their formulation and use as pharmaceuticals.
EP-A-0498722 describes quinoline derivatives as angiotensin A2 and endothelin inhibitors.
The modes of action of phosphodiesterases and also tumour necrosis factors (TNF), and the therapeutic utilities of inhibitors thereof, are described in WO-A-9744036 and U.S. Pat. No. 5804588, the contents of which are incorporated herein by reference. These publications specifically disclose quinoline carboxamides having such inhibitory activity.
This invention provides novel compounds having therapeutic utility, in particular for the treatment of disease states associated with proteins which mediate cellular activity, for example by inhibiting TNF and/or PDE IV. According to the invention, the compounds are of formula (i): 
wherein
R1 is CH3, CH2F, CHF2 or CF3;
R2 is CH3 or CF3;
R3 is F, Cl, Br, CN or CH3; and
R4 is H, F, Cl, Br, CN or CH3;
or a pharmaceutically-acceptable salt thereof.
In summary, the compounds of the invention are N-oxides of the corresponding free bases which are disclosed, some specifically, in WO-A-9744036. The novel compounds have superior solubility, improved metabolic stability, and an improved pharmacokinetic profile. The compound of Example 8 is particularly preferred.
This invention provides also a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.